Journal Article

Effect of Connective Tissue Growth Factor on Hypoxia-Inducible Factor 1α Degradation and Tumor Angiogenesis

Cheng-Chi Chang, Ming-Tsai Lin, Been-Ren Lin, Yung-Ming Jeng, Szu-Ta Chen, Chia-Yu Chu, Robert J. Chen, King-Jen Chang, Pan-Chyr Yang and Min-Liang Kuo

in JNCI: Journal of the National Cancer Institute

Volume 98, issue 14, pages 984-995
Published in print July 2006 | ISSN: 0027-8874
Published online July 2006 | e-ISSN: 1460-2105 | DOI: http://dx.doi.org/10.1093/jnci/djj242
Effect of Connective Tissue Growth Factor on Hypoxia-Inducible Factor 1α Degradation and Tumor Angiogenesis

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Background: Connective tissue growth factor (CTGF) inhibits the metastatic activity of human lung cancer cells in a mouse model; however, the mechanism of this modulation is unclear. We investigated the role of angiogenesis in this process. Methods: CL1-5 and A549 human lung adenocarcinoma cells were stably transfected with vectors containing CTGF or hypoxia-inducible factor (HIF) 1α or with vector controls. Transfected cells were injected into nude mice (n = 10 per group), and tumor growth, metastasis, and mouse survival were measured. Excised xenograft tumors and primary human lung adenocarcinomas (n = 24) were subjected to immunohistochemistry with antibodies to the endothelial cell marker CD31 and to CTGF. Expression of HIF-1α and vascular endothelial growth factor (VEGF) A was assessed in vitro by using reporter gene assays. Cells were transiently transfected with HIF-1α mutant and antisense arrest-defective 1 protein (ARD-1), and HIF-1α acetylation was assayed by immunoprecipitation. All statistical tests were two-sided. Results: Xenograft tumors derived from CTGF transfectants grew more slowly than those from control-transfected cells and had reduced expression of HIF-1α and VEGF-A, vascularization (as assessed by CD31 expression), and metastasis (all P<.001). Xenograft tumors derived from CTGF-overexpressing cells that were transfected with HIF-1α had higher VEGF-A expression than CTGF-overexpressing xenografts. Mice with CTGF/HIF-1α xenografts had lower survival than mice carrying CTGF-overexpressing xenografts (CL1-5/Neo, mean = 69.6 days, 95% confidence interval [CI] = 53.9 to 85.3 days versus CL1-5/CTGF, mean = 102.1 days, 95% CI = 92.1 to 112.1 days; P = .001, CL1-5/CTGF, mean = 102.1 days, 95% CI = 92.1 to 112.1 days versus CL1-5/CTGF/HIF-1α, mean = 81.7 days, 95% CI = 66.5 to 96.9 days; P = .011, CL1-5/Neo, mean = 69.6 days, 95% CI = 53.9 to 85.3 days versus CL1-5/CTGF/HIF-1α, mean = 81.7 days, 95% CI = 66.5 to 96.9 days; P = .122). Tumors of patients with the same disease stage but with high CTGF protein expression had reduced microvessel density compared with tumors with low expression. Transfection with antisense-ARD1 decreased the level of acetylated HIF-1α and restored HIF-1α and VEGF-A expression in CTGF-overexpressing cells. Conclusion: CTGF inhibition of metastasis involves the inhibition of VEGF-A–dependent angiogenesis, possibly by promoting HIF-1α protein degradation.

Journal Article.  10912 words.  Illustrated.

Subjects: Medical Oncology

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